Identification of Biologically Diverse Tetrahydronaphthalen‐2‐ols through the Synthesis and Phenotypic Profiling of Chemically Diverse, Estradiol‐Inspired Compounds

Abstract

Combining natural product fragments to design new scaffolds with unprecedented bioactivity is a powerful strategy for the discovery of tool compounds and potential therapeutics. However, the choice of fragments to couple and the biological screens to employ remain open questions in the field. By choosing a primary fragment containing the A/B ring system of estradiol and fusing it to nine different secondary fragments, we were able to identify compounds that modulated four different phenotypes: inhibition of autophagy and osteoblast differentiation, as well as potassium channel and tubulin modulation. The latter two were uncovered by using unbiased morphological profiling with a cell-painting assay. The number of hits and variety in bioactivity discovered validates the use of recombining natural product fragments coupled to phenotypic screening for the rapid identification of biologically diverse compounds.

Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library

“…To explore the steric and electronic requirements for 5-HT 2C binding and validate the predicted binding mode, analogues with varying substituents and functional group replacements primarily on the chromanone ring were prepared (Scheme 2). From 16c, reduction of the ketone to the methylene (19) or to the alcohol (20) surprisingly resulted in reduced 5-HT 2C antagonist activity (Supporting Information Table S2). This may be due to the ketone's electronic effect on the already electron rich aryl system, although the precise reason for this effect remains unclear and could not be discerned by our modelling.…”

“…The acidic layer was washed with excessive saturated NaHCO 3 and extracted with DCM (2 × 30 mL), and the collected organic layer was dried over Na 2 SO 4 and concentrated in vacuo to yield a solid product without further purification. (19). To a solution of 16c (81.9 mg, 0.3 mmol) in acetic acid (6.0 mL) was added zinc (588.4 mg, 9.0 mmol), and the mixture was stirred at 80 °C under nitrogen atmosphere for 18 h. The mixture was filtered off through a Celite plug, the filtrate was concentrated, the resulting residue was added saturated NaHCO 3 (20 mL) and extracted with DCM (2 × 10 mL), the combined organic layer was dried with NaSO 4 , and the solvent was evaporated under reduced pressure to yield a brown oil compound (64.8 mg, 80% (20).…”

“…Several strategies for accessing chemically and biologically diverse compounds have been reported in the last two decades, including (privileged) diversity-oriented synthesis (DOS), , biology-oriented synthesis (BIOS), , function-oriented synthesis, ring distortion, modification and C–H functionalization of NPs, − and most recently pseudo-NP synthesis. , Recently, we employed a combination of several of the abovementioned strategies in the synthesis of diverse, sterol-inspired libraries comprising two steroidal primary fragments fused to up to 14 secondary fragments, resulting in the identification of potent and selective inhibitors of cholesterol transport proteins, as well as hedgehog signaling and autophagy inhibitors. , We reasoned that alkaloid primary fragments could be fused to secondary NP fragments to synthesize a diverse, alkaloid-inspired library for the identification of selective modulators of monoaminergic GPCRs. Herein, we report the synthesis of a library including tropanes and quinuclidines as privileged, primary fragments, fused to a diverse set of secondary fragments (Figure ).…”

“…= 22.5 Hz), 103.05 (d, J = 24.8 Hz), 80.17, 68.06, 52.59, 42.77, 28.57 19. F NMR (377 MHz, CDCl 3 ): δ −105.1.…”

Collective Synthesis of Sarpagine and Macroline Alkaloid‐Inspired Compounds

“…High similarities to bioactivity cluster profiles, i. e. >80 %, suggest similar modes of action and thereby facilitate the annotation of uncharacterized compounds without prior knowledge of the top biosimilar reference compounds. So far, 12 bioactivity cluster profiles have been defined that include biological targets related to AKT/PI3K/MTOR, Aurora kinases, BET, DNA synthesis, HDAC, HSP90, Na + /K + ATPases, [36] lysosomotropism/cholesterol homeostasis regulation (LCH), protein synthesis, pyrimidine biosynthesis, [37] tubulin, and uncoupling of the mitochondrial proton gradient.…”